DETERMINATIONS OF GLUCOSE TURNOVER AND OXIDATION IN NORMAL VOLUNTEERS AND SEPTIC PATIENTS USING STABLE AND RADIO-ISOTOPES

Rates of glucose turnover and oxidation were isotopically determined in normal volunteers (n= 16) and in severely septic patients (n= 10). Glucose turnover was determined using primed constant infusions of either 6-³H- or 6,6-d-glucose and glucose oxidation with either U-¹⁴C-glucose or U-¹³C-glucose after appropriate priming of the bicarbonate pool. Basal rates of glucose turnover, oxidation, and plasma clearance were significantly higher in the septic patients than in the volunteers. During glucose infusion (4 mg/kg·min) endogenous glucose production was virtually abolished in the volunteers (94±4% suppression). There was significantly less suppression in the septic patients (39±7%); (p<0.01). In addition, the percentage of available glucose oxidized (i.e. the percentage of glucose uptake oxidized) was significantly less in the septic patients. When the patients were studied during total parenteral nutrition (at a similar rate of glucose infusion) there was no further suppression of endogenous glucose production compared with that seen during 2h of glucose infusioin. However, the percentage of available glucose oxidized increased significantly. From these studies it is concluded that (i) septic patients continue to have ongoing consumption of host tissue despite receiving either glucose infusion or total parenteral nutrition, and (ii) septic patients are less able to oxidize glucose than normal volunteers when infused for only 2 h. However, adaptation occurs with the longer infusion time used in total parenteral nutrition (TPN).     

Extracerebral hematoma in association with dural substitute

The authors present a patient who developed an acute hemorrhage around a Silastic dural substitute 13 weeks after excision of a meningioma and implantation of the graft. The relevant literature is reviewed.     

The 20,000 Da variant of human growth hormone does not bind to growth hormone receptors in human liver

The 20,000 Da variant of human growth hormone (hGH) (20K) exhibited no specific binding to hGH receptors in human liver plasma membranes. This contrasts with the 22,000 Da form of human growth hormone (22K), which bound with high affinity to the same hepatic receptor preparation. Since the liver is considered a major target organ for the somatogenic pathway of growth hormone action, this finding implies that in humans the 20K form plays little role in that pathway. The homologous hormone-receptor system examined here yielded results that differ from heterologous receptor binding experiments in animals. The differences are likely explained by the presence in non-primate mammals of more than one type of growth hormone receptor with varied specificities. In man, the 20K form of growth hormone may have a biological role distinct from that of the main 22K form of growth hormone.     

Patients'' observations of bioprosthetic valve failure: "my heart is honking, doctor".

Audible cardiac murmurs are uncommon and may indicate severe native valve dysfunction. In six patients with bioprosthetic mitral valves audible honking systolic murmurs suddenly developed. Doppler echocardiography showed characteristic striated regurgitant signals. At operation each prosthesis had torn cusps. New audible murmurs and striated Doppler signals originating from mitral bioprosthetic valves are indicators of cusp tears. Recognition of this is important because early detection of prosthetic valve dysfunction may improve subsequent surgical outcome.     

Genomics and proteomics analysis of acetaminophen toxicity in mouse liver.

Overdose of acetaminophen (APAP) causes severe centrilobular hepatic necrosis in humans and experimental animals. Here, to explore its mechanism, we administered APAP at subtoxic (150 mg/kg ip) and toxic (500 mg/kg ip) doses to overnight fasted mice. Animals were sacrificed at different time points from 15 min to 4 h postinjection. We assessed liver toxicity by plasma ALT activity and by electron microscopy. Using nylon filter arrays and RTQPCR, we performed genomics analysis in liver. We ran proteomics on liver mitochondrial subfractions using the newly developed quantitative fluorescent 2D-DIGE method (Amersham Pharmacia Biotech UK Limited). As soon as 15 min postinjection, centrilobular hepatocyte mitochondria were already slightly enlarged and GSH total content dropped by a third at top dose. GM-CSF mRNA, which is a granulocyte specific gene likely coming from resident Kupffer cells, was also induced to its maximum of 3-fold at both doses. Chaperone proteins Hsp10 and Hsp60 were readily decreased by half in mitochondria at both doses, most likely by leaking into cytoplasm. Although APAP is known as an apoptotic trigger, no apoptosis was observed at any time point. Most of the protein changes in mitochondria were present at 15 min postinjection, thus preceding most of the gene regulations. The decrease of ATP synthase subunits and beta-oxidation pathway proteins indicated a loss of energy production. As the morphology of mitochondria was also affected very early at top dose, we concluded that APAP toxicity was a direct action of its known reactive metabolite NAPQI, rather than a consequence of gene regulation. However, the latter will either worsen the toxicity or lead toward cell recovery depending on the cellular damage level.     

Too stringent patient selection criteria in a clinical trial of alpha-blockers reduce the value of the results.

The patient selection criteria in a clinical trial of an alpha-blocker for the treatment of benign prostatic hypertrophy were such that 85% of the patients on the waiting lists of 4 hospitals had to be excluded. The value of such a trial is discussed. Trial protocols should be designed to allow the enrollment of patients truly representative of the patients for which the treatment is intended.     

Rat small intestinal morphology and tissue regulatory peptides: effects of high dietary fat.

Sprague-Dawley rats (3 weeks old) were fed on isoenergetic diets in which 40% of the total energy was provided as fat either in the form of butter (high saturated fat), olive oil (high monounsaturated fat) or maize oil (high polyunsaturated fat), with one group on low-fat (10% of total energy) standard diet as a control. Animals were killed after 8.4 (se 0.8) weeks by cardiac puncture. Similar pieces of jejunum and ileum were prepared for morphometric studies. Extracts of tissue from the proximal and distal segments of the whole small intestine from four animals per group were assayed using established techniques for enteroglucagon, motilin, neurotensin, somatostatin, substance P and vasoactive intestinal peptide (VIP). We found that maize oil and olive oil increased villus height: crypt depth ratio in both jejunum and ileum. Maize oil increased tissue concentrations of somatostatin (P less than 0.05) and substance P (P less than 0.005) in the proximal segment. Both maize oil and olive oil increased tissue concentrations of neurotensin and substance P (P less than 0.005) in the distal segments. These observations may explain the improvement of intestinal absorption of fluid following supplementation with polyunsaturated fat.     

Prolonged paralysis associated with long-term pancuronium use

We cared for a 4-year-old patient who had undergone orthotopic liver transplantation and was placed on a ventilator for respiratory distress associated with Pneumocystis carinii pneumonia. The neuromuscular blocking agent pancuronium bromide 1.0-1.2 mg every hour as needed was used to facilitate artificial ventilation for 40 days. On discontinuation of pancuronium, the patient experienced severe, generalized neuromuscular dysfunction. Because no improvement was seen for 2 weeks, the acetylcholinesterase inhibitors edrophonium and pyridostigmine were instituted. Shortly thereafter the patient's condition began to improve. Gradual improvement occurred over 3-4 months and the patient has since returned to baseline neurologic function. We suggest that long-term pancuronium use was the cause of the patient's prolonged paralysis. The improvement experienced after the initiation of antidotal therapy strongly supports our proposal.